{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:52:38Z","timestamp":1787068358400,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Astilbin, as a compound of flavonoids, exerts anti-inflammation, antioxidation, and immune-suppression activities. Decreased activation of NF-\u03baB and p38 MAPK and increased activation of SOCS3 and AMPK have been found in astilbin-treated cells. However, what molecules are docked by astilbin to initiate signaling cascades and result in functional changes remains unknown. In the study, we found that astilbin efficiently suppressed TNF-\u03b1 production and increased CCR9 and CD36 expression of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells.\n                    <jats:italic>In vivo<\/jats:italic>\n                    administration of astilbin repressed the occurrence of type 1 diabetes mellitus in non-obese diabetic mice. The PPAR\u03b3\/SOCS3, PPAR\u03b3\/PTEN, and PPAR\u03b3\/AMPK signaling pathways were substantially activated and played key roles in astilbin-induced downregulation of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell functions. Transcriptome sequencing results confirmed the changes of signaling molecules involved in the immune system, inflammatory responses, and indicated variations of multiple enzymes with oxidant or antioxidant activities. Astilbin directly induced cytoplasmic ROS production of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells\n                    <jats:italic>ex vivo<\/jats:italic>\n                    , but had no effects on mitochondrial ROS and mitochondrial weight. When cellular ROS was depleted, astilbin-treated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells remarkably reversed the expression of TNF-\u03b1, IFN-\u03b3, CCR9, CD36, and signaling molecules (PPAR\u03b3, PTEN, p-AMPK, and SOCS3). Based on bioinformatics, two P450 enzymes (CYP1B1 and CYP19A1) were selected as candidate receptors for astilbin. CYP1B1 was identified as a real docking protein of astilbin in ROS production by AutoDock Vina software analysis and surface plasmon resonance assay. Collectively, astilbin downregulates effector CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell activities\n                    <jats:italic>via<\/jats:italic>\n                    the CYP1B1\/ROS\/PPAR\u03b3 pathway, which firmly supports its potential use in the treatment of inflammation.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2022.848957","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T05:13:13Z","timestamp":1652677993000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Astilbin Activates the Reactive Oxidative Species\/PPAR\u03b3 Pathway to Suppress Effector CD4+ T Cell Activities via Direct Binding With Cytochrome P450 1B1"],"prefix":"10.3389","volume":"13","author":[{"given":"Shizhen","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guotao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxia","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbing","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijuan","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105853","DOI":"10.1016\/j.phrs.2021.105853","article-title":"The Pivotal Role of Nrf2 Activators in Adipocyte Biology","volume":"173","author":"Annie-Mathew","year":"2021","journal-title":"Pharmacol. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"566","DOI":"10.2337\/db21-0612","article-title":"Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells that Mark Progression to Type 1 Diabetes","volume":"71","author":"Bediaga","year":"2022","journal-title":"Diabetes."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3578","DOI":"10.1158\/0008-5472.CAN-12-4018","article-title":"SOCS3 Transactivation by PPAR\u03b3 Prevents IL-17-driven Cancer Growth","volume":"73","author":"Berger","year":"2013","journal-title":"Cancer Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1007\/s00011-003-1179-3","article-title":"Astilbin Suppresses Collagen-Induced Arthritis via the Dysfunction of Lymphocytes","volume":"52","author":"Cai","year":"2003","journal-title":"Inflamm. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fimmu.2014.00058","article-title":"SOCS3, a Major Regulator of Infection and Inflammation","volume":"5","author":"Carow","year":"2014","journal-title":"Front. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"703972","DOI":"10.3389\/fimmu.2021.703972","article-title":"Targeting Mitochondrial-Derived Reactive Oxygen Species in T Cell-Mediated Autoimmune Diseases","volume":"12","author":"Ch\u00e1vez","year":"2021","journal-title":"Front. Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/j.biopha.2018.07.072","article-title":"Astilbin Inhibits High Glucose-Induced Autophagy and Apoptosis through the PI3K\/Akt Pathway in Human Proximal Tubular Epithelial Cells","volume":"106","author":"Chen","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B8","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/s41392-021-00563-x","article-title":"Activation of Transmembrane Receptor Tyrosine Kinase DDR1-STAT3 Cascade by Extracellular Matrix Remodeling Promotes Liver Metastatic Colonization in Uveal Melanoma","volume":"6","author":"Dai","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"B9","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nature10189","article-title":"Oncogene-induced Nrf2 Transcription Promotes ROS Detoxification and Tumorigenesis","volume":"475","author":"DeNicola","year":"2011","journal-title":"Nature."},{"key":"B10","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.intimp.2015.12.035","article-title":"Astilbin Inhibits Th17 Cell Differentiation and Ameliorates Imiquimod-Induced Psoriasis-like Skin Lesions in BALB\/c Mice via Jak3\/Stat3 Signaling Pathway","volume":"32","author":"Di","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.fct.2013.10.045","article-title":"Astilbin Protects Diabetic Rat Heart against Ischemia-Reperfusion Injury via Blockade of HMGB1-dependent NF-\u039ab Signaling Pathway","volume":"63","author":"Diao","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.bbrc.2014.02.136","article-title":"Induction of TGF-\u03b2 and IL-10 Production in Dendritic Cells Using Astilbin to Inhibit Dextran Sulfate Sodium-Induced Colitis","volume":"446","author":"Ding","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.ejmech.2017.04.042","article-title":"Inhibitors of Cytochrome P450 (CYP) 1B1","volume":"135","author":"Dutour","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1016\/j.jaci.2005.08.032","article-title":"Astilbin Inhibits Contact Hypersensitivity through Negative Cytokine Regulation Distinct from Cyclosporin A","volume":"116","author":"Fei","year":"2005","journal-title":"J. Allergy Clin. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0124002","DOI":"10.1371\/journal.pone.0124002","article-title":"Decrease of Functional Activated T and B Cells and Treatment of Glomerulonephitis in Lupus-Prone Mice Using a Natural Flavonoid Astilbin","volume":"10","author":"Guo","year":"2015","journal-title":"Plos One."},{"key":"B16","doi-asserted-by":"publisher","first-page":"106143","DOI":"10.1016\/j.intimp.2019.106143","article-title":"Astilbin Promotes the Induction of Regulatory NK1.1- CD4+ NKG2D+ T Cells through the PI3K, STAT3, and MAPK Signaling Pathways","volume":"81","author":"Han","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.coi.2011.08.004","article-title":"CD4 T Cells and Their Antigens in the Pathogenesis of Autoimmune Diabetes","volume":"23","author":"Haskins","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1016\/j.cmet.2019.01.019","article-title":"Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function","volume":"29","author":"Kaufmann","year":"2019","journal-title":"Cell Metab."},{"key":"B19","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.jep.2006.07.007","article-title":"Effects of Astilbe Thunbergii Rhizomes on Wound Healing Part 1. Isolation of Promotional Effectors from Astilbe Thunbergii Rhizomes on Burn Wound Healing","volume":"109","author":"Kimura","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.pharmthera.2017.03.007","article-title":"Potential Role of CYP1B1 in the Development and Treatment of Metabolic Diseases","volume":"178","author":"Li","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1039\/c9tx00222g","article-title":"Astilbin Attenuates Cerebral Ischemia\/reperfusion Injury by Inhibiting the TLR4\/MyD88\/NF-\u039ab Pathway","volume":"8","author":"Li","year":"2019","journal-title":"Toxicol. Res. (Camb)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"106571","DOI":"10.1016\/j.intimp.2020.106571","article-title":"Astilbin Protects against Cerebral Ischaemia\/reperfusion Injury by Inhibiting Cellular Apoptosis and ROS-NLRP3 Inflammasome axis Activation","volume":"84","author":"Li","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1248\/bpb.b13-00968","article-title":"Antidepressant Activity of Astilbin: Involvement of Monoaminergic Neurotransmitters and BDNF Signal Pathway","volume":"37","author":"Lv","year":"2014","journal-title":"Biol. Pharm. Bull."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051529","article-title":"The CD36-Ppar\u03b3 Pathway in Metabolic Disorders","volume":"19","author":"Mar\u00e9chal","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.ejphar.2015.11.004","article-title":"Fatty Acids, Eicosanoids and PPAR Gamma","volume":"785","author":"Marion-Letellier","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.jneuroim.2016.07.016","article-title":"Astilbin Ameliorates Experimental Autoimmune Myasthenia Gravis by Decreased Th17 Cytokines and Up-Regulated T Regulatory Cells","volume":"298","author":"Meng","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s13555-016-0101-1","article-title":"t-Flavanone Improves the Male Pattern of Hair Loss by Enhancing Hair-Anchoring Strength: A Randomized, Double-Blind, Placebo-Controlled Study","volume":"6","author":"Nagasawa","year":"2016","journal-title":"Dermatol Ther. (Heidelb)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: an Overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1002\/bdd.2000","article-title":"In Vitro and In Vivo Characterization of CYP Inhibition by 1-aminobenzotriazole in Rats","volume":"37","author":"Parrish","year":"2016","journal-title":"Biopharm. Drug Dispos."},{"key":"B30","doi-asserted-by":"publisher","first-page":"6247306","DOI":"10.1155\/2018\/6247306","article-title":"Smilax Aristolochiifolia Root Extract and its Compounds Chlorogenic Acid and Astilbin Inhibit the Activity of \u03b1-Amylase and \u03b1-Glucosidase Enzymes","volume":"2018","author":"P\u00e9rez-N\u00e1jera","year":"20182018","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"104894","DOI":"10.1016\/j.phrs.2020.104894","article-title":"Astilbin: A Promising Unexplored Compound with Multidimensional Medicinal and Health Benefits","volume":"158","author":"Sharma","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e5039","DOI":"10.1002\/bmc.5039","article-title":"Inhibitory Effects of Astilbin, Neoastilbin and Isoastilbin on Human Cytochrome CYP3A4 and 2D6 Activities","volume":"35","author":"Shi","year":"2021","journal-title":"Biomed. Chromatogr."},{"key":"B33","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1159\/000514594","article-title":"Astilbin Protects against Carbon Tetrachloride-Induced Liver Fibrosis in Rats","volume":"106","author":"Sun","year":"2021","journal-title":"Pharmacology."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1002\/bio.4065","article-title":"Interaction Study of Astilbin, Isoastilbin and Neoastilbin toward CYP2D6 by Multi-Spectroscopy and Molecular Docking","volume":"36","author":"Tao","year":"2021","journal-title":"Luminescence."},{"key":"B35","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1007\/s10571-016-0405-9","article-title":"The Effects of Astilbin on Cognitive Impairments in a Transgenic Mouse Model of Alzheimer's Disease","volume":"37","author":"Wang","year":"2017","journal-title":"Cell Mol. Neurobiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1211\/0022357023033","article-title":"Astilbin Prevents Concanavalin A-Induced Liver Injury by Reducing TNF-Alpha Production and T Lymphocytes Adhesion","volume":"56","author":"Wang","year":"2004","journal-title":"J. Pharm. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1016\/j.biopha.2016.07.025","article-title":"Astilbin Improves Potassium Oxonate-Induced Hyperuricemia and Kidney Injury through Regulating Oxidative Stress and Inflammation Response in Mice","volume":"83","author":"Wang","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"B38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/s40659-019-0255-2","article-title":"Astilbin Reduces ROS Accumulation and VEGF Expression through Nrf2 in Psoriasis-like Skin Disease","volume":"52","author":"Wang","year":"2019","journal-title":"Biol. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1146\/annurev-biochem-082411-113907","article-title":"Pten","volume":"83","author":"Worby","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"B40","doi-asserted-by":"publisher","first-page":"110450","DOI":"10.1016\/j.biopha.2020.110450","article-title":"Astilbin Combined with Lipopolysaccharide Induces IL-10-producing Regulatory B Cells via the STAT3 Signalling Pathway","volume":"129","author":"Xu","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"B41","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1002\/jsfa.10669","article-title":"Astilbin Lowers the Effective Caffeine Dose for Decreasing Lipid Accumulation via Activating AMPK in High-Fat Diet-Induced Obese Mice","volume":"101","author":"Yang","year":"2021","journal-title":"J. Sci. Food Agric."},{"key":"B42","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.biopha.2017.05.127","article-title":"Astilbin Decreases Proliferation and Improves Differentiation in HaCaT Keratinocytes","volume":"93","author":"Zhang","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B43","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1016\/j.biopha.2017.08.115","article-title":"Erhuang Formula Ameliorates Renal Damage in Adenine-Induced Chronic Renal Failure Rats via Inhibiting Inflammatory and Fibrotic Responses","volume":"95","author":"Zhang","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1007\/s12272-016-0857-y","article-title":"Astilbin Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting the Expression of Macrophage Inhibitory Factor in Rats","volume":"40","author":"Zhang H B","year":"2017","journal-title":"Arch. Pharm. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/s11596-009-0215-0","article-title":"The Inhibitory Effect of Astilbin on the Arteriosclerosis of Murine Thoracic Aorta Transplant","volume":"29","author":"Zhao","year":"2009","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3892\/ijmm.2019.4188","article-title":"Mitochondrial Electron Transport Chain, ROS Generation and Uncoupling (Review)","volume":"44","author":"Zhao","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.intimp.2018.11.004","article-title":"Neuroprotective Effects of Astilbin on MPTP-Induced Parkinson's Disease Mice: Glial Reaction, Alpha-Synuclein Expression and Oxidative Stress","volume":"66","author":"Zhu","year":"2019","journal-title":"Int. Immunopharmacol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.848957\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T05:13:18Z","timestamp":1652677998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.848957\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,16]]},"references-count":47,"alternative-id":["10.3389\/fphar.2022.848957"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.848957","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,16]]},"article-number":"848957"}}